Telaprevir (VX-950) is a novel hepatitis C virus (HCV) NS3-4A protease inhibitor exhibits potent antiviral activities in HCV replicon cells. The NS3-4A serine protease of hepatitis C virus (HCV) is essential for viral replication and therefore has been one of the most attractive targets for developing specific antiviral agents against HCV. Telaprevir (VX-950) is currently in clinical development for the treatment of hepatitis C. Incubation with VX-950 resulted in a time- and dose-dependent reduction of HCV RNA and proteins in replicon cells. Moreover, following a 2-week incubation with VX-950, a reduction in HCV RNA levels of 4.7 log(10) was observed, and this reduction resulted in elimination of HCV RNA from replicon cells, since there was no rebound in replicon RNA after withdrawal of the inhibitor. The combination of VX-950 and alpha interferon was additive to moderately synergistic in reducing HCV RNA in replicon cells with no significant increase in cytotoxicity. The benefit of the combination was sustained over time: a 4-log(10) reduction in HCV RNA level was achieved following a 9-day incubation with VX-950 and alpha interferon at lower concentrations than when either VX-950 or alpha interferon was used alone. The combination of VX-950 and alpha interferon also suppressed the emergence of in vitro resistance mutations against VX-950 in replicon cells.
|Cell lines||Huh-7 cells|
|Preparation method||Huh-7 cells harboring an autonomously replicating, subgenomic HCV replicon of the Con1 strain (19) were maintained in Dulbecco's modified Eagle's medium (DMEM), 10% heat-inactivated fetal bovine serum (FBS), 2 mM l-glutamine, and nonessential amino acids (JRH Biosciences, Lenexa, KS), plus 0.25 mg/ml G418 (Invitrogen, Carlsbad, CA). The subgenomic HCV replicon also encodes a neomycin phosphotransferase, which allows selective growth of HCV replicon-containing Huh-7 cells over HCV replicon-negative Huh-7 cells in the presence of G418. The VX-950 concentrations at which the HCV RNA level in the replicon cells is reduced by 50% (IC50) or by 90% (IC90) or the cell viability is reduced by 50% (CC50), were determined in HCV Con1 subgenomic replicon cells (19) using 4-parameter curve fitting (SoftMax Pro) as described previously (15, 18). Briefly, the replicon cells were incubated with compounds diluted in DMEM containing 2% FBS and 0.5% DMSO (without G418) at 37°C. Total cellular RNA was extracted using an RNeasy-96 kit (QIAGEN, Valencia, CA), and the copy number of the HCV RNA was determined in a quantitative, real-time, multiplex reverse transcription-PCR (QRT-PCR, or Taqman) assay (18). The cytotoxicity of compounds in the HCV replicon cells was measured under the same experimental settings using the tetrazolium-based cell viability assay as described before.|
|Concentrations||0, 0.03, 0.1, 0.3, 1, 3, 10 μ M|
|Incubation time||48 h|
|Animal models||Mouse model for HCV NS3-4A serine protease|
|Dosages||10, 25, 75, 150, or 300 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease.
Perni RB, et al. Antimicrob Agents Chemother. 2006 Mar;50(3):899-909. PMID: 16495249.
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